Ovary

Progesterone Receptor Antagonists and Statins Decrease De Novo Cholesterol Synthesis and Increase Apoptosis in Rat and Human Periovulatory Granulosa Cells In Vitro

Abstract
Progesterone receptor (PR) stimulation promotes survival in rat and human periovulatory granulosa cells. To investigate the mechanisms involved, periovulatory rat granulosa cells were incubated in vitro with or without the PR antagonist Org 31710. Org 31710 caused the expected increase in apoptosis, and expression profiling using cDNA microarray revealed regulation of several groups of genes with functional and/or metabolic connections. This regulation included decreased expression of genes involved in follicular rupture, increased stress responses, decreased angiogenesis and decreased cholesterol synthesis. A decreased cholesterol synthesis was verified in experiments with both rat and human periovulatory granulosa cells treated with the PR antagonists Org 31710 or RU 486 by measuring incorporation of ¹⁴C-acetate into cholesterol, cholesterol ester and progesterone. Correspondingly, specific inhibition of cholesterol synthesis in periovulatory rat granulosa cells using HMG-CoA reductase inhibitors (lovastatin, mevastatin or simvastatin) increased apoptosis, measured as DNA fragmentation and caspase-3/-7 activity. The increase in apoptosis caused by simvastatin was reversed by addition of the cholesterol synthesis intermediary mevalonic acid. These results show that PR antagonists reduce cholesterol synthesis in periovulatory granulosa cells and that cholesterol synthesis is important for granulosa cell survival.

Key words: Mechanisms of Hormone Action • Ovary • Apoptosis • Follicular development • Progesterone receptor

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